Roche vs CIPLA: The Contours of Section 3(d)


The Roche vs CIPLA litigation gives us an excellent opportunity to examine the contours of section 3(d). Please read our previous posts, please see here.

Section 3(d) reads as below:

“the mere discovery of a new form of a known substance which does not result in increased efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such process results in a new product or employs at least one new reactant.

Explanation: For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy.”

In essence, section 3(d) aims to prevent a phenomenon commonly referred to as “ever-greening”. The underlying assumption is that derivatives, such as salt forms, polymorphs, isomers etc that are structurally similar to known pharmaceutical substances are likely to be functionally equivalent as well–and if this is not the case and the new form of an existing substance works better than the old form, it is up-to the patent applicant to demonstrate this and claim a patent.

To this extent, section 3(d) draws a distinction between “evergreening” and incremental innovation. By making derivates with added efficacy patentable, section 3(d) encourages sequential developments of existing products or technologies that help bring in improved products to the market.

Now, in Roche vs CIPLA, the earlier known substance is Gefatinib. Roche then claims a structurally similar compound, Erlotinib. The question essentially is: is Erlotinib a derivative of Gefatinib? If it is a “derivative”, then under the explanation to section 3(d), unless such
derivative demonstrates “a significant difference in property with regard to efficacy”, it will be construed as the “same substance” as Gefatinib. It appears that even if

As a colleague of mine who wishes to remain anonymous and whom I deeply respect for his knowledge on both the Indian pharmaceutical industry and patent law writes and tells me:

“Structurally, they both have the common 4-quinazolinamine nucleus but the substitution patterns are quite different. They both are derivatives of 4-quinazolinamine, but are not really derivatives of each other (though it could be tenuously argued that any two compounds that have even the slightest of similarities could be interconverted.)

Such an argument could then be reduced ad absurdum to say that only one compound in any series of compounds having some structural similarity and acting by the same mchansim whould e patentable. That’ll truly be absurd. It should also be noted that (a) erlotinib has an additional indication (combination with gemcitabine for pancreatic cancer) and (b) erlotinib ha it is own NCE exclusivity in the USA which shows that the FDA considered it to have a different active moiety from gefitinib which was marketed earlier.”

I tend to agree with him. A compound that has some amount structural similarity with a prior compound cannot always be treated as it’s “derivative”. If this were always the case, then a large number of pharma compounds could be said to be “carbon” derivatives of some sort and therefore subject to section 3(d)!! Note in particular his last sentence which suggests that even if Erlotinib were treated as a derivative of Gefatinib (marketed as Iressa and a patent over which was recently rejected in India), then it is likely that since it has an additional use (pancreatic cancer) over and above Gefatinib, it ought to be able to fulfill the condition of “enhanced efficacy” under section 3(d).

Shamnad Basheer

Shamnad Basheer

Prof (Dr) Shamnad Basheer founded SpicyIP in 2005. He is currently the Honorary Research Chair of IP Law at Nirma University and a visiting professor of law at the National Law School (NLS), Bangalore. He is also the Founder of IDIA, a project to train underprivileged students for admissions to the leading law schools. He served for two years as an expert on the IP global advisory council (GAC) of the World Economic Forum (WEF). In 2015, he received the Infosys Prize in Humanities in 2015 for his work on legal education and on democratising the discourse around intellectual property law and policy. The jury was headed by Nobel laureate, Prof Amartya Sen. Professional History: After graduating from the NLS, Bangalore Professor Basheer joinedAnand and Anand, one of India’s leading IP firms. He went on to head their telecommunication and technology practice and was rated by the IFLR as a leading technology lawyer. He left for the University of Oxford to pursue post-graduate studies, completing the BCL, MPhil and DPhil as a Wellcome Trust scholar. His first academic appointment was at the George Washington University Law School, where he served as the Frank H Marks Visiting Associate Professor of IP Law. He then relocated to India in 2008 to take up the MHRD Chaired Professorship in IP Law at WB NUJS, a leading Indian law school. Prof Basheer has published widely and his articles have won awards, including those instituted by ATRIP and the Stanford Technology Law Review. He is consulted widely by the government, industry, international organisations and civil society on a variety of IP issues. He also serves on several government committees.

22 comments.

  1. AvatarVarun

    Check recently posted article at Patent Circle, which infact trying to explore complex chemistry behind 4-anilinoquinazoline family. Both Gefitinib & Erlotinib belongs to same family of 4-anilioquinazoline.

    Reply
  2. AvatarShamnad Basheer

    Dear Varun,

    Great post, but I’m still left wondering: is Erlotinib a derivative of Gefatinib? They may come from the same family–but they are different substances. And in fact, the US FDA has conferred on Erlotinib the status of a “new chemical entity”. Just because they come from the same family (parents), can they (siblings) be said to be derivatives of each other?

    Reply
  3. AvatarAnonymous

    …. then it is likely that since it has an additional use (pancreatic cancer) over and above Gefatinib, it ought to be able to fulfill the condition of “enhanced efficacy” under section 3(d).

    wanted to know whether an “additional use” is equivalent to “enhanced efficacy”? Will it not come under “new use”.

    Reply
  4. AvatarAnonymous

    Do you mean to say “increased efficacy” and “new use” are the same!!!When you say that Erlotinib has increased eficacy when compared to Gefatinib it means that the bioavailability of Erlotinib should be higher!!!!If that is the case then according to section 3(d) Erlotinib should be patentable. But the fact is Erlotinib has a different use which was not found for Gefatinib. In that case according to section 3(d) Erlotinib is not patentable. Please post your comment on this……

    Reply
  5. AvatarShamnad Basheer

    Thanks for your comment. But I don’t think you’ve understood my post.

    If this is a case of “new use”, then Erlotinib qualifies as a “new form” that “differs significantly in property with regard to efficacy”.

    A different “efficacy” altogether (“new use”) will certainly constitute a “difference in property” with regard to efficacy. Nowhere does the explanation state that it has to be the same “efficacy”!!

    Reply
  6. AvatarAnonymous

    at this point i have a doubt regarding patentability. For example inventor A has a patent on a compound X with 40% efficacy used for treating say blood cancer. Later on an inventor B comes with a compound Y whose structure is entirely different from that of X but with efficacy same or say less than or slightly greater than the compound X which is also used for treating blood cnacer. In this situation will the inventor B gets a patent for his invention according to Indian patent law. Please clarify.

    Reply
  7. AvatarShamnad Basheer

    If Y’s structure is completely different and it is not “obvious” to a skilled person to derive Y from X or any other prior art, then Y ought to get the patent. It is a different substance altogether and therefore does not qualify as “derivative” under section 3(d). It doesnt matter that it demonstrates only the same efficacy as an earlier compound. Since it is a “new” and non obvious compond, it ought to be granted patent protection.

    Reply
  8. AvatarAnonymous

    If that is the case will not the product marketability of inventor A who filed first and got a patent be affected, as both the compounds serve the same purpose? Moreover the purpose of a patent is to encourage new inventions and to leverage R&D activities. This seems to be somewhat discouraging inventor A right!!!!!Your suggestions please!!!!

    Reply
  9. AvatarVarun

    Dear Anonymous,

    Obviously “increased efficacy” and “new use” are not the same, at least in context of section 3(d). As far as “increased efficacy” is concerned, section 3(d) particularly does not limit it to bioavailability (until and unless expressly provided in explanation or pen-down by Indian Courts). In fact, it would be absurd restricting ‘efficacy’ to bioavailability because technically bioavailability is more a concept associated to formulation development rather than active ingredient itself. I personally believe the word “efficacy” should have broader scope to include improved stability, eliminating toxicity, physiological changes, improved pharmacokinetic properties, solubility enhancement and so on.

    Now coming back to Erlotinib & Gefitinib, Erlotinib has additional indication compared to Gefitinib, which has no significance in assessment of patentability under section 3(d). Same additional indication may also be found in Gefitinib (considering both belong to same class of drugs) provided that company conducts additional trials to establish that. Question is whether Erlotinib should be granted patent under section 3(d) over prior art known Gefitinib compound?

    Regards,

    Varun

    Reply
  10. AvatarShamnad Basheer

    Thanks Varun,

    You wrote:

    “Now coming back to Erlotinib & Gefitinib, Erlotinib has additional indication compared to Gefitinib, which has no significance in assessment of patentability under section 3(d). Same additional indication may also be found in Gefitinib (considering both belong to same class of drugs) provided that company conducts additional trials to establish that”.

    Isn’t that a specious argument? for one, do all compounds in the same class always have the same indications?? Secondly, we don’t have any facts right now stating that Gefatinib shows this additional indication. If it doesn’t, then quite obviously Erlotinib is able to show “significant differences in property with regard to efficacy” AND therefore does not fall within the purview of non patentable subject matter under section 3(d). Of course, it might still be held to be “obvious” from the structre of Gefatinib, but that is a different question/analysis altogether.

    Reply
  11. AvatarShamnad Basheer

    Dear Anonymous:

    You said “Moreover the purpose of a patent is to encourage new inventions and to leverage R&D activities. This seems to be somewhat discouraging inventor A right!!!!”

    Well, if I come up with an improvement or a better technology than A, am I not hitting at the “incentive” to A then? A gets a patent for a limited time, because A gave something new and inventive to the world. If someone else comes with another invention that the market picks up, A cannot stop that–and the purpose of patent law is to encourage inventive activitiy (from anyone) and not to preserve teh monopoly of A, in the face of other other technical advances.

    Reply
  12. AvatarVarun

    Dear Shamnad,

    “New use” particularly does not mean that Erlotinib qualifies as a “new form”, even same compound can have “new use” but that does not mean the compound will be considered “new form.”

    “Efficacy” and “new use” are two different aspects of chemical compound. Efficacy relates more to physiological (chemical and physical) properties of a compound, whereas “new use” relates more to therapeutic/clinical application/indication.

    Regards,

    Varun

    Reply
  13. AvatarShamnad Basheer

    Dear Varun,

    As to whether it is a “new form” or “derivative” or not was already addressed in the earlier parts of these exchanges. Kindly go through them. The later exchanges were premised on teh assumption that Erlotinib is not a derivative of Gefatinib–an assumption that even you seem to support in your blog posts. So let’s go one step further in the debate and ask ourselves whether if Erlotinib is a new derivative, it is still hit by “efficacy” requirements…

    Reply
  14. AvatarVarun

    Dear Anonymous,

    Although Erlotinib is not a derivative of Gefitinib, but still let us consider Erlotinib a chemical derivative of Gefitinib then according to section 3(d) Erlotinib is not patentable provided it does not show enhancement over known efficacy of Gefitinib. Now the question is what do you consider by efficacy? And what empirical parameters patentee needs to provide to differentiate efficacy under section 3(d)?

    Now considering if efficacy has to be shown via comparative clinical studies with respect to drug administered to patients, then comparative parameters will include pharmacokinetic studies (such as extent and rate of absorption) and bioavailability. I hope you agree with this!

    Factors such as pharmacokinetics largely depend on drug compound physical properties such as hydrophobicity, pKa and solubility whereas bioavailability mainly depends on drug formulation, drug administration (with or without food), and action of other drugs/food. Now do you feel such comparisons will suffice the ‘efficacy’ requirements under section 3(d)?

    Gefitinib is available in 250mg dosage form whereas Erlotinib in 25mg, 100mg, and 150mg dosage forms. According to labelled information, Gefitinib has mean oral bioavailability of 60% and is not significantly altered by food whereas Erlotinib has mean oral bioavailability of 60% and is substantially increased by food to almost 100%. There may be some other clinical pharmacological data which may differ between Gefitinib & Erlotinib. Do you think such empirical parameters will be sufficient to state Erlotinib has improved efficacy over Gefitinib?

    Your comments …

    Regards,

    Varun

    Reply
  15. AvatarAnonymous

    Dear Shamnad,

    What I mean to say is Compounds A and B are structurally different but they have the same use and efficacy. A was filed first and was granted patent. B was filed few months later. Just because B is novel and non-obvious will the patent law grants patent!!!!I can understand that if this is the case the public will be more benefited as the price may go down. But the law seems to have de-motivated compound A inventor. I think patent law encourages inventions of this type if it grand patent for compound B after the expiration of the first filed patent (compound A). But if it allows during the term of first filed and granted compound A invention wont the law seems to have de-motivating compound A inventor.

    Your suggestions please….

    Reply
  16. AvatarAnon2

    Dear All
    Sorry for the late comment – but as I was reading the above post and comments, I was wondering about the ‘new use for a known substance’ bar under section 3(d) –> does this not point to the principle of patent law that once a product is patented, all used (whether known or not at the time of patenting the product) are covered by the patent? If this is indeed the case also in India, then how can a new use (treating pancreatic cancer) lead to the grant of a separate patent?
    Also, to Shamnad – does your opinion on ‘new use’ change in the light of the recent Monsanto decision where the court refused a patent relating to a Cold Shock protein on the ground that the patent by Monsanto merely claimed a new use of the cold shock protein? Spicy Ip has also blogged on the Monsanto case but does not refer back to your analysis (http://spicyipindia.blogspot.com/2008/02/roche-vs-cipla-final-day.html)

    Reply
  17. AvatarAnon2

    Sorry there were some errors in my earlier comment – so I am re-posting:
    Dear All
    Sorry for the late comment – but as I was reading the above post and comments, I was wondering about the ‘new use for a known substance’ bar under section 3(d) –> does this not point to the principle of patent law that once a product is patented, all uses (whether known or not at the time of patenting the product) are covered by the patent? If this is indeed the case also in India, then how can the identification of a new use (e.g. treating pancreatic cancer) lead to the grant of a separate patent?
    Also, to Shamnad – does your opinion on ‘new use’ change in the light of the recent Monsanto decision in India where the IPAB refused a patent relating to a Cold Shock protein under sec. 3(d) on the ground that the patent by Monsanto merely claimed a new use of the well known cold shock protein? Spicy Ip has also blogged on the Monsanto case but does not refer back to your analysis (http://spicyipindia.blogspot.com/2008/02/roche-vs-cipla-final-day.html)

    Reply

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